scholarly journals The within-host dynamics of African trypanosome infections

2015 ◽  
Vol 370 (1675) ◽  
pp. 20140288 ◽  
Author(s):  
Keith R. Matthews ◽  
Richard McCulloch ◽  
Liam J. Morrison
Keyword(s):  
Antigenic Variation ◽  
Blood Feeding ◽  
Tsetse Flies ◽  
Host Animal ◽  
Term Survival ◽  
African Trypanosomes ◽  
Transmission Potential ◽  
Infection Dynamics ◽  
Animal Populations ◽  
Developmental Progression

African trypanosomes are single-celled protozoan parasites that are capable of long-term survival while living extracellularly in the bloodstream and tissues of mammalian hosts. Prolonged infections are possible because trypanosomes undergo antigenic variation—the expression of a large repertoire of antigenically distinct surface coats, which allows the parasite population to evade antibody-mediated elimination. The mechanisms by which antigen genes become activated influence their order of expression, most likely by influencing the frequency of productive antigen switching, which in turn is likely to contribute to infection chronicity. Superimposed upon antigen switching as a contributor to trypanosome infection dynamics is the density-dependent production of cell-cycle arrested parasite transmission stages, which limit the infection while ensuring parasite spread to new hosts via the bite of blood-feeding tsetse flies. Neither antigen switching nor developmental progression to transmission stages is driven by the host. However, the host can contribute to the infection dynamic through the selection of distinct antigen types, the influence of genetic susceptibility or trypanotolerance and the potential influence of host-dependent effects on parasite virulence, development of transmission stages and pathogenicity. In a zoonotic infection cycle where trypanosomes circulate within a range of host animal populations, and in some cases humans, there is considerable scope for a complex interplay between parasite immune evasion, transmission potential and host factors to govern the profile and outcome of infection.

Escape mechanisms of African trypanosomes: why trypanosomosis is keeping us awake

Parasitology ◽  
2014 ◽  
Vol 142 (3) ◽  
pp. 417-427 ◽  
Author(s):  
JENNIFER CNOPS ◽  
STEFAN MAGEZ ◽  
CARL De TREZ
Keyword(s):  
Immune Response ◽  
Trypanosoma Brucei ◽  
Parasitic Infection ◽  
Mammalian Host ◽  
Tsetse Flies ◽  
African Trypanosomes ◽  
Transmission Potential ◽  
Highly Sensitive ◽  
Commercially Important ◽  
And Control

SUMMARYAfrican trypanosomes have been around for more than 100 million years, and have adapted to survival in a very wide host range. While various indigenous African mammalian host species display a tolerant phenotype towards this parasitic infection, and hence serve as perpetual reservoirs, many commercially important livestock species are highly disease susceptible. When considering humans, they too display a highly sensitive disease progression phenotype for infections withTrypanosoma brucei rhodesienseorTrypanosoma brucei gambiense, while being intrinsically resistant to infections with other trypanosome species. As extracellular trypanosomes proliferate and live freely in the bloodstream and lymphatics, they are constantly exposed to the immune system. Due to co-evolution, this environment however no longer poses a hostile threat, but has become the niche environment where trypanosomes thrive and obligatory await transmission through the bites of tsetse flies or other haematophagic vectors, ideally without causing severe side infection-associated pathology to their host. Hence, African trypanosomes have acquired various mechanisms to manipulate and control the host immune response, evading effective elimination. Despite the extensive research into trypanosomosis over the past 40 years, many aspects of the anti-parasite immune response remain to be solved and no vaccine is currently available. Here we review the recent work on the different escape mechanisms employed by African Trypanosomes to ensure infection chronicity and transmission potential.

scholarly journals Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Christopher Batram ◽  
Nicola G Jones ◽  
Christian J Janzen ◽  
Sebastian M Markert ◽  
Markus Engstler
Keyword(s):  
Trypanosoma Brucei ◽  
Histone Methylation ◽  
Antigenic Variation ◽  
Tsetse Fly ◽  
Developmental Competence ◽  
Surface Glycoprotein ◽  
G1 Phase ◽  
African Trypanosomes ◽  
Developmental Progression ◽  
Expression Site

We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness.

African trypanosomes: the genome and adaptations for immune evasion

2011 ◽  
Vol 51 ◽  
pp. 47-62 ◽  
Author(s):  
Gloria Rudenko
Keyword(s):  
Immune Evasion ◽  
Cell Biology ◽  
Antigenic Variation ◽  
Critical Role ◽  
Sub Saharan Africa ◽  
Surface Glycoprotein ◽  
Tsetse Flies ◽  
African Trypanosomes ◽  
Genes Encoding ◽  
Sub Saharan

The African trypanosome Trypanosoma brucei is a flagellated unicellular parasite transmitted by tsetse flies that causes African sleeping sickness in sub-Saharan Africa. Trypanosomes are highly adapted for life in the hostile environment of the mammalian bloodstream, and have various adaptations to their cell biology that facilitate immune evasion. These include a specialized morphology, with most nutrient uptake occurring in the privileged location of the flagellar pocket. In addition, trypanosomes show extremely high rates of recycling of a protective VSG (variant surface glycoprotein) coat, whereby host antibodies are stripped off of the VSG before it is re-used. VSG recycling therefore functions as a mechanism for cleaning the VSG coat, allowing trypanosomes to survive in low titres of anti-VSG antibodies. Lastly, T. brucei has developed an extremely sophisticated strategy of antigenic variation of its VSG coat allowing it to evade host antibodies. A single trypanosome has more than 1500 VSG genes, most of which are located in extensive silent arrays. Strikingly, most of these silent VSGs are pseudogenes, and we are still in the process of trying to understand how non-intact VSGs are recombined to produce genes encoding functional coats. Only one VSG is expressed at a time from one of approximately 15 telomeric VSG ES (expression site) transcription units. It is becoming increasingly clear that chromatin remodelling must play a critical role in ES control. Hopefully, a better understanding of these unique trypanosome adaptations will eventually allow us to disrupt their ability to multiply in the mammalian bloodstream.

scholarly journals Tsetse Fly Saliva Accelerates the Onset of Trypanosoma brucei Infection in a Mouse Model Associated with a Reduced Host Inflammatory Response

2006 ◽  
Vol 74 (11) ◽  
pp. 6324-6330 ◽  
Author(s):  
Guy Caljon ◽  
Jan Van Den Abbeele ◽  
Benoît Stijlemans ◽  
Marc Coosemans ◽  
Patrick De Baetselier ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Inflammatory Responses ◽  
Blood Feeding ◽  
Immunoglobulin M ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Tsetse Flies ◽  
Feeding Site ◽  
African Trypanosomes ◽  
Cytokine Tumor Necrosis Factor

ABSTRACT Tsetse flies (Glossina sp.) are the vectors that transmit African trypanosomes, protozoan parasites that cause human sleeping sickness and veterinary infections in the African continent. These blood-feeding dipteran insects deposit saliva at the feeding site that enables the blood-feeding process. Here we demonstrate that tsetse fly saliva also accelerates the onset of a Trypanosoma brucei infection. This effect was associated with a reduced inflammatory reaction at the site of infection initiation (reflected by a decrease of interleukin-6 [IL-6] and IL-12 mRNA) as well as lower serum concentrations of the trypanocidal cytokine tumor necrosis factor. Variant-specific surface glycoprotein-specific antibody isotypes immunoglobulin M (IgM) and IgG2a, implicated in trypanosome clearance, were not suppressed. We propose that tsetse fly saliva accelerates the onset of trypanosome infection by inhibiting local and systemic inflammatory responses involved in parasite control.

scholarly journals Developmental competence and antigen switch frequency can be uncoupled in Trypanosoma brucei

2019 ◽  
Vol 116 (45) ◽  
pp. 22774-22782 ◽  
Author(s):  
Kirsty R. McWilliam ◽  
Alasdair Ivens ◽  
Liam J. Morrison ◽  
Monica R. Mugnier ◽  
Keith R. Matthews
Keyword(s):  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Experimental Studies ◽  
Developmental Competence ◽  
Parasite Development ◽  
Mammalian Host ◽  
Mechanical Transmission ◽  
African Trypanosomes ◽  
Infection Dynamic ◽  
Developmental Capacity

African trypanosomes use an extreme form of antigenic variation to evade host immunity, involving the switching of expressed variant surface glycoproteins by a stochastic and parasite-intrinsic process. Parasite development in the mammalian host is another feature of the infection dynamic, with trypanosomes undergoing quorum sensing (QS)-dependent differentiation between proliferative slender forms and arrested, transmissible, stumpy forms. Longstanding experimental studies have suggested that the frequency of antigenic variation and transmissibility may be linked, antigen switching being higher in developmentally competent, fly-transmissible, parasites (“pleomorphs”) than in serially passaged “monomorphic” lines that cannot transmit through flies. Here, we have directly tested this tenet of the infection dynamic by using 2 experimental systems to reduce pleomorphism. Firstly, lines were generated that inducibly lose developmental capacity through RNAi-mediated silencing of the QS signaling machinery (“inducible monomorphs”). Secondly, de novo lines were derived that have lost the capacity for stumpy formation by serial passage (“selected monomorphs”) and analyzed for their antigenic variation in comparison to isogenic preselected populations. Analysis of both inducible and selected monomorphs has established that antigen switch frequency and developmental capacity are independently selected traits. This generates the potential for diverse infection dynamics in different parasite populations where the rate of antigenic switching and transmission competence are uncoupled. Further, this may support the evolution, maintenance, and spread of important trypanosome variants such as Trypanosoma brucei evansi that exploit mechanical transmission.

scholarly journals Targeting the Variable Surface of African Trypanosomes with Variant Surface Glycoprotein-Specific, Serum-Stable RNA Aptamers

2003 ◽  
Vol 2 (1) ◽  
pp. 84-94 ◽  
Author(s):  
Mihaela Lorger ◽  
Markus Engstler ◽  
Matthias Homann ◽  
H. Ulrich Göringer
Keyword(s):  
Antigenic Variation ◽  
Sleeping Sickness ◽  
Rna Aptamers ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Parasite Protein ◽  
African Trypanosomes ◽  
Variable Surface ◽  
New Strategy

ABSTRACT African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.

Antigenic variation in African trypanosomes

Science ◽  
1994 ◽  
Vol 264 (5167) ◽  
pp. 1872-1873 ◽  
Author(s):  
P Borst ◽  
G Rudenko
Keyword(s):  
Antigenic Variation ◽  
African Trypanosomes

DNA rearrangements and antigenic variation in Trypanosoma equiperdum: multiple expression-linked sites in independent isolates of trypanosomes expressing the same antigen

1983 ◽  
Vol 3 (3) ◽  
pp. 399-409
Author(s):  
S Longacre ◽  
U Hibner ◽  
A Raibaud ◽  
H Eisen ◽  
T Baltz ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanism ◽  
Antigenic Variation ◽  
Cdna Probe ◽  
Surface Glycoprotein ◽  
Dna Rearrangements ◽  
African Trypanosomes ◽  
Trypanosoma Equiperdum ◽  
Variant Surface Glycoproteins ◽  
Multiple Expression

African trypanosomes resist the immune response of their mammalian hosts by varying the surface glycoprotein which constitutes their antigenic identity. The molecular mechanism of this antigenic variation involves the successive activation of a series of genes which code for different variant surface glycoproteins (VSGs). We have studied the expression of two VSG genes (those of VSG-1 and VSG-28) in Trypanosoma equiperdum, and we report the following findings. (i) The expression of both VSG genes is associated with the duplication and transposition of corresponding basic copy genes. (ii) The duplicated transposed copy appears to be the expressed copy. (iii) Although there are multiple genes which cross-hybridize with the VSG-1 cDNA probe, only one of these appears to be used as a template for the expression-linked copy in four independent BoTat-1 clones. (iv) Analysis of the genomic environments of the expressed VSG-1 genes from each of four independently derived BoTat-1 trypanosome clones revealed that there are at least three different sites into which the expression-linked copy can be inserted.

scholarly journals Glucose Signaling Is Important for Nutrient Adaptation during Differentiation of Pleomorphic African Trypanosomes

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Yijian Qiu ◽  
Jillian E. Milanes ◽  
Jessica A. Jones ◽  
Rooksana E. Noorai ◽  
Vijay Shankar ◽  
...  
Keyword(s):  
Life Cycle ◽  
Glucose Sensing ◽  
Negative Regulator ◽  
Bloodstream Form ◽  
Tsetse Flies ◽  
Insect Vector ◽  
Rapid Reduction ◽  
African Trypanosomes ◽  
Procyclic Form ◽  
African Trypanosome

ABSTRACT The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its life cycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites were rapidly killed as glucose concentrations fell, while short stumpy bloodstream form parasites persisted to differentiate into the insect-stage procyclic form parasite. The rate of differentiation was lower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and nonmetabolizable glucose analogs, and these parasites were found to have upregulated amino acid metabolic pathway component gene expression. In summary, glucose transitions from the primary metabolite of the blood-stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but also an important signaling molecule. IMPORTANCE As the African trypanosome Trypanosoma brucei completes its life cycle, it encounters many different environments. Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Here, we describe how the blood-dwelling life cycle stages of the African trypanosome, which consume glucose to meet their nutritional needs, respond differently to culture in the near absence of glucose. The proliferative long slender parasites rapidly die, while the nondividing short stumpy parasite remains viable and undergoes differentiation to the next life cycle stage, the procyclic form parasite. Interestingly, a sugar analog that cannot be used as an energy source inhibited the process. Furthermore, the growth of procyclic form parasite that resulted from the event was inhibited by glucose, a behavior that is similar to that of parasites isolated from tsetse flies. Our findings suggest that glucose sensing serves as an important modulator of nutrient adaptation in the parasite.

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